Brexit… it’s getting closer…

Ivowen have provided some practical guidance and documents below, which may help you prepare for Brexit for products authorised by the DCP and MRP procedures.

Take our Brexit quiz to see if you are ready.

Do you still need to change your MAH(s) in any of the EU Member States because of Brexit?

If so, refer to the following updated guidance issued in January 2019 which details the documentation and requirements to submit a Marketing Authorisation Holder transfer:

CMDh guidance on Brexit, Jan 2019

If you need any clarification or support to complete a Marketing Authorisation Holder transfer, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

Is the UK your current RMS?

If so, you need to initiate an RMS switch as soon as possible. The guidance issued in July 2018 along with the template issued in June 2018 is required to complete this process. This template needs to be completed and sent to a specific e-mail address at the proposed new RMS. The list of contacts points to send the completed template is provided below:

Guidance:

CMDh guidance on changing RMS

Template for RMS change

List of RMS contacts can be found in the excel spread sheet in the link Contact Points, which can be found here:

MS contact points

If you need any clarification or support a RMS switch, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

 

Do you need to change your UK batch release site, etc., if it currently within the UK?

If so, you can refer to the updated guidance document issued in December 2018, which provides information on the type of variation that is required to change functions such as batch release site(s), QC testing site(s), packaging site(s), deletion of site(s) for batch release and changes to the QP for Pharmacovigilance (QPPV) and PSMF where these functions still reside within the UK:

CMDh practical guidance for Brexit & DCP/MRP

If you need any clarification or support to complete variations to support changes needed as a result of Brexit, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

Do you supply product to Cyprus?

If so, the Cypriot Competent Authority has issued a newsletter to Stakeholders on the 14 January 2019 which lists 105 products authorised via an exceptional marketing authorisation affected by Brexit which are considered critical. The Drugs Council in Cyprus recommends that pharmaceutical companies register these products via an exceptional marketing authorisation using another reference state other that the UK.

Cyprus list of essential medicines

If you need any clarification or support to complete an Exceptional Marketing Authorisation to avoid no supply of these critical products on the Cypriot market, Ivowen will gladly assist you in a timely manner.  Contact us for more information or to make an enquiry.

 

 Written by Marian Winder

To 2019 and beyond (Brexit)…

With the festive season upon us and 2019 on the horizon, Ivowen are setting our sights on the year ahead.  So what’s going on in 2019 and beyond, including and excluding Brexit…

What’s happening in early 2019?

We will be attending the Medicines for Europe Regulatory and Scientific Affairs and Pharmacovigilance conferences in January and we encourage you to contact us before mid-January with any specific questions you might like us to ‘ask the regulators’.

Brexit follows quickly on the tail of the new year, and we will all be hopefully ready and able for this new challenge.  Take our Brexit quiz here to see if you are Brexit ready and contact us to help.

What’s happening in later on in 2019?

We are also looking forward to attending the annual TOPRA symposium this year, hosted in Dublin, and we hope to see you at our stand to discuss how we can assist you with your regulatory needs in 2019 and beyond.

What about us?

Ivowen consists of an amazing team with extensive experience of the pharmaceutical industry. Our aim is to understand our customer’s needs and offer services that meet those needs in a timely and efficient way.
As part of EuDRAcon, a pan European network of regulatory consultants, we can provide expert advice on all matters regulatory for the EU and beyond, including Brexit

We hope that in 2019 Ivowen can help you with your specific and unique requests.

And for now…

The office will be closed from the afternoon of Friday 21st December 2018 until Wednesday 2nd January 2019. Merry Christmas and a Happy New Year for 2019!

For more information on Ivowen’s services and how we can help you, contact us

 

 

Written by Mary Canning

HPRA’s support as you prepare for Brexit……

Brexit in:

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The Health Products Regulatory Authority (HPRA) of Ireland is geared up and ready to support MA holders as they prepare for Brexit.

 

What happens if UK leaves the EU with no deal?

The implications of Brexit with regard to the UK’s role in the licensing of medicines will be determined by the terms of the ongoing exit negotiations. However, in accordance with Directives 2001/82/EC and 2001/83/EC:

  • For marketing authorisations issued through the mutual recognition procedure (MRP) or decentralised procedure (DCP), the Reference Member State (RMS) must be based in the EU/EEA.
  • The marketing authorisation holder (MAH) must be located within the EU/EEA.
  • MAHs will need to ensure that their EU qualified person responsible for pharmacovigilance (QPPV) and their pharmacovigilance system master file (PSMF) are located within the EU/EEA.
  • The batch release/testing site must be located within the EU/EEA.

 

HPRA are working “extraordinarily” hard on preparing for all scenarios

HPRA are Brexit ready

– Willing to act as RMS for all products where Ireland (IE) is currently CMS and a change of RMS is required. No fees will apply to the process for changing RMS to IE. The HPRA commits to an efficient and simple process for handling these requests (for example allowing the inclusion of multiple products in one request where applicable).

– To encourage the use of multilingual labelling the HPRA will proactively work with other European regulators to help optimise opportunities for multilingual labelling. The HPRA ‘Guide to labels and leaflets of Human Medicines’ has been updated (Oct 2018) to give specific guidance on the development of multilingual labelling

– HPRA MAH transfer procedures have recently been changed to allow MAHs up to 6 months to implement packaging changes following issue of the transferred authorisation, for Brexit related transfers. In addition the HPRA no longer requires stock to be recalled from wholesaler level six months following the issue of the transferred authorisation/ licence/registration.

 

Timeline for changing RMS

Can be completed within a matter of days. The critical issue will be the timing of when the change in RMS should occur as it is required to occur when there are no open regulatory activities for a product.

 

Procedures for MAHs to transfer MAH to EU/EEA based MAH

The transfer procedure must be used where the legal entity of an authorisation/licence holder is changed as marketing authorisations are transferred to a new company number. It is possible to transfer the MAH while there are ongoing/open variations. If the transfer is processed/issued, the new MA holder details will transfer onto the open/ongoing variations

  • Bulk transfers are accepted by the HPRA for Brexit and reduced fees apply.
  • New PA number is provided in advance of application.
  • Word version of an updated package leaflet is acceptable.

If the only changes proposed relate to MAH details and a new PA number, an Article 61(3) application is not required. However, if there are additional changes to the labels and package leaflet an Article 61(3) application must be submitted. This can be submitted in parallel to the transfer.

 

Medical devices containing an ancillary medicinal substance

Transfers of medical devices containing a medicinal ancillary substance with a valid CE certificate are considered administrative only. Transfers typically take less than 30 days from validation of the submission to be completed. No fees will apply to this transfer process.

 

Parallel Product Authorisations

If the UK is listed as one of a number of source countries on a PPA, this will need to be removed by way of a type IA variation (category 4).

Where the holder of PPA is located within the UK, the authorisation will need to be transferred to holder located within the EEA.

Qualified person certification of repackaging activity must take place within the EEA. Variations to change the site of batch certification can be submitted using the PPA variation category No 9a and 9b.

 

Variations to Marketing Authorisations to change Qualified Person Responsible for Pharmacovigilance (QPPV), manufacturing site or/and batch release sites.

Any variations required for a marketing authorisation (MA), e.g change in location of QPPV or site of batch release, should be completed prior to the date of the UK’s departure from the EU (prior to the 29 March 2019).

Changes in the QPPV, including contact details (telephone, and fax numbers, postal address and email address) may, for medicinal products for human use, be updated through the Article 57 database only (without the need for a variation)

Changes to the location of the PSMF (street, city, postcode, country) may be updated through the Article 57 database only (without the need for a variation)

 

 

Are you in search of advice and support on Brexit?

Please contact us, Ivowen are available to offer advice and support on HPRA compliance.

 

Written by Nanda Naik

 

 

 

 

 

 

 

Are you Brexit ready?

Brexit in:

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Test your knowledge, take our Brexit quiz here 

What do you want to do next?  Do you want to continue to market your product in the EU only, or are you interested in both the EU and UK markets?  Read on to find out what you need to do for both scenarios.

If you would like to continue to market your product in the EU there are a few things that need to be finalised before Brexit on the 29th March 2019:

 

Reference Member State (RMS transfer)

This should have been done yesterday(!) The time it takes depends on the requested RMS’s workload.

Since July 2018 the MHRA is no longer accepting new applications with UK as RMS. However there are some currently authorised products wherein the UK is still the RMS.

If you have products and the UK is currently the RMS then it is vital a RMS transfer is initiated immediately. If there is only one CMS then this CMS should become the RMS (submission required). If there is more than one CMS, the preferred CMS needs to be consulted and a request sent asking them to be RMS. It is the responsibility of the MAH to secure a new RMS. The timeline for such transfers are solely dependent on the workload of the requested RMS.

 

Marketing Authorisation Holder (MAH) transfer

Needs to be done immediately – the time it takes is dependent on where the application is submitted.

From the 29th March 2019 the MAH for a product licensed in an EU Member State (MS) other than the UK must be based in the EU. Therefore if the MAH is currently based in the UK there needs to be a MAH transfer to one based in the EU.

  • If this involves purely an address change (i.e. the marketing authorisation holder remains the same legal entity but they have an address in the EU) then this is a simple type IAin (A.1).
  • If the new MAH is a different legal entity then the MAH transfer must follow the guidelines of the currently registered RMS and CMS, at the very least documents such as transfer agreement, proof of establishment, , power of attorney(s), Pharmacovigilance (PV) update, etc., should be in place before submission of the request.

 

Batch release

Needs to be done within the next 4-8 weeks unless a product is a biological / immunological product in which case submission needs to be immediate.

Products that only have batch release and quality control testing sites for finished product in the UK will have to change the batch release and testing sites for their EU products. For products that have other batch release and testing sites the MAH may choose to delete the UK site(s) or may choose to replace them. For finished products manufactured in the UK an importation site (in EEA) will need to be introduced. In many cases, a single site can perform manufacturing, testing, importation and/or batch release activities.

The timelimes will follow the type IA/IB or type II (biological / immunological product) categories depending on what change is applied for. Please see https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/c_2013_2008/c_2013_2008_doc/c_2013_2804_en.doc

 

PV

Needs to be done asap and in association with any MAH transfers – usually a type IA or type IAin

 

The Qualified Person for Pharmacovigilance (QPPV) and Pharmacovigilance Site Master File (PSMF) must be based in the EU/EEA.

 

If you wish to continue to market the product in the UK in addition to the EU:

The MHRA have stated that after Brexit, all currently approved authorisations will be transferred into national procedures and will remain valid.

If an application is in-progress at the time of Brexit the application will need to be submitted to the MHRA again as a national application in the case of CP procedures and that for MR or DC procedures a transitional provision will be made.  HOWEVER, this is contingent on a Brexit deal that allows for a transition period.  This has not yet been agreed.

To ensure the product can remain on the market / licensed, the UK are proposing the following if there is a no-deal Brexit

  • a MAH should be established in the UK by the end of 2020. Until then, the MHRA will require a contact in the UK. A Change of Ownership will need to be submitted to MHRA to change from an EU MAH to a UK MAH for UK MAs
  • the Qualified Person for Pharmacovigilance (QPPV) should be established in the UK on day one, although those without a current UK presence will have until the end of 2020 at the latest to do so, but would nevertheless be required to make arrangements for providing the MHRA with access to the relevant safety data related to UK Marketing Authorisations (MAs) at any time. Companies may choose to have the EU QPPV take on responsibility for UK MAs until the UK QPPV can be established. A variation should be submitted to the MHRA to change QPPV. Exact details of this will be consulted upon
  • a Qualified Person (QP) for products manufactured in the UK or directly imported into the UK from outside a country on a designated country list (whitelist) must reside and operate in the UK. A QP for products manufactured in a country on a whitelist or manufactured in a third country and imported into the UK from a country on a whitelist can reside in a country on the whitelist.

(https://www.gov.uk/government/publications/how-medicines-medical-devices-and-clinical-trials-would-be-regulated-if-theres-no-brexit-deal/how-medicines-medical-devices-and-clinical-trials-would-be-regulated-if-theres-no-brexit-deal)

 

Do you need help with any of the above or any other regulatory issue?

Contact us!  We’re here to help.

 

Written by Emily Fletcher

Emily Fletcher

 

Company Announcement – Majella Ryan FTOPRA

Majella Ryan FTOPRA

Ivowen are pleased to announce that Fellowship of The Organisation for Professionals in Regulatory Affairs (FTOPRA) has been conferred on Majella Ryan.  According to TOPRA:

The award of a Fellowship is intended to recognise a contribution in which the individual has used his/her professional knowledge and experience to influence, guide or develop the profession in a proactive way.
While clearly the individual’s regulatory experience and current senior position achieved are important, what is also looked for is a consistent record of activities or influences extending beyond the confines of the individual’s day-to-day activities.”

Majella Ryan has been in the regulatory affairs business for over 20 years and in this time has worked in both small and large multi-national companies, setting up Ivowen in 2002. Since then, Majella was involved in the set-up of TOPRA in Ireland, acting as the inaugural Chair in 2001/2011, as well as speaking at various conferences and providing extensive regulatory training to companies around the world.  In addition, Majella is actively engaged in the publication and explanation of regulatory and guidance updates via Ivowen’s website, and via Ivowen’s EU network, EuDRAcon.  As part of Ivowen’s daily work, Majella is involved in the high level regulatory strategy and support of complex projects and products like biosimilars, paediatric investigation plans and clinical trials, eCTD implementation, regulatory pathways to approval, Brexit planning, and much more.

For more information on Ivowen’s services and how we can help you, contact us.

 

 

 

Preparing for Brexit

As the date for the withdrawal of the UK (also known as Brexit) from the EU approached closer, it pays to hope for the best and prepare for the worst.  With this in mind, the EMA have issued a guidance document on “Practical guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralised procedure, EMA, 19 June 2018” to prepare for the UK’s exit from the EU by the 30 March 2019.  

 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/11/WC500239369.pdf

 

What does it mean?

For marketing authorisation applications (MAAs) that are expected to receive a Commission Decision (i.e. be approved) after 29 March 2019, the QPPV, PSMF (for medicines for human use), batch release sites, batch control sites, intended OMCL (if applicable) and nominated local representatives for Member States other than UK must be located in in the Union (EEA).

As published on the EMA website on the 10 July, a recent European Medicines Agency (EMA) survey shows that marketing authorisation holders for more than half (58%) of the 694 centrally authorised products (CAPs) with an important step in their regulatory processes in the United Kingdom (UK), are on track with their regulatory planning to ensure that their marketing authorisation remains valid once the UK leaves the European Union (EU).

This also means that 42% are NOT ready… Are you one of the 42%

The EMA urges those companies who have not yet informed EMA of their Brexit preparedness plans to do so as soon as possible to mitigate any risks to the continuous supply of medicines for human and veterinary use within the EU.

 

We can help…

Ivowen can help Clients prepare to implement the required changes by providing the following services:

  • Provide practical guidance on what needs to be in place by the above date to address situations where the UK is the current MAH, batch release site, batch control sites, location of QPPV& PSMF, transfer of orphan designation, etc.
  • Act as a MAH in the EU
  • Provide Pharmacovigilance (QPPV) services in the EU
  • Provide Pharmacovigilance System Master File and backup services located in the EU
  • Assist Clients in selecting and transferring RMS to another EU member state where the UK is current MAH
  • Preparation of Brexit related variations to be ready for above timelines
  • Assistance in changes needed to Product Information to reflect changes such as new MAH, batch release site(s), amend names of local representatives

Please contact us for further information at any time.

 

 

HPRA now part of the EU-US Mutual Recognition Agreement (MRA)

As of 1st June 2018, Ireland became one of the recognised member states in the Mutual Recognition Agreement (MRA) between the EU and the US FDA.

What is the MRA?

The Mutual Recognition Agreement (MRA) is an agreement between countries concerning the conformity assessment of regulated products.  From the pharmaceutical point of view, this means that there is an agreement between certain countries that recognises each country’s/member state’s ability to carry out good manufacturing practise (GMP) inspections to a standard at least equivalent to the other country’s/member state’s own.

The EU and US authorities MRA entered into force on 1st November 2017.  Part of this agreement was a transition phase for recognition of EU Member States until July 2019. Tan audit of the HPRA’s GMP inspection systems in May 2017 was observed by the US FDA.  Consequently, the US has recognised the HPRA as an EU authority that has the capability, capacity and procedures to carry out GMP inspections at an equivalent level to the US FDA. As a consequence of this review, Ireland has been included on the list of recognised member states on 1st June 2018.

What does having an MRA mean?

MRAs allow EU authorities and their counterparts to:

  • rely on each other’s GMP inspection system giving rise to
    • a reduction in the number of US FDA inspections required on manufacturers in Ireland
    • a reduction in the number of HPRA inspections required on US manufacturers
  • share information on inspections and quality defects with each other;
  • waive batch (re)testing of products on import into their territories, resulting in reduced costs for companies on the analytical testing front.

What does it cover?

The initial scope includes:

  • human medicines, which incorporates intermediates and in-process materials,
  • biologicals, including immunological and biotherapeutic products and
  • active pharmaceutical ingredients (APIs) also known as drug substances.

Excluded for the moment are:

  • biological medicines, including vaccines, advanced therapy medicinal products, and plasma derived medicines and
  • veterinary medicines.

Full details on the scope of products included in the EU-US mutual recognition agreement can be found here: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001843.jsp&mid=WC0b01ac058005f8ac

The announcement by the HPRA can be found here:  https://tinyurl.com/IE-MRA

What do you need to do?

Unfortunately, not everything is mutually recognised yet.

If you have manufacturing sites in the US and are importing into Ireland, you still have have to do full batch release testing on  medicinal products imported into the EU from the US.  Once all MS’s GMP Inspectorates have been successfully assessed by the FDA, then QC release testing will no longer be required.  The reverse also holds true.  Therefore, batch testing and QC testing sites can be deleted from your licence as desired at this stage.

More information in the HPRA’s Newletter here.

We can help…

Ivowen can advise you on the requirements and assist you with any of the updates and variations that you might have.

Please contact us for further information at any time.

Written by Majella Ryan

Excipient guideline update

The updated Annex to “Excipients in the labelling and package leaflet of medicinal products for human use” guideline was published on the 09/10/2017. This updated Annex in all EU languages can be found here:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001646.jsp

In addition, Notice to Applicants Volume 2C has been updated in March 2018 to reflect this updated annex.

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/c/guidelines_excipients_march2018_en.pdf

What does it mean?

Marketing Authorisation (MA) Holders for approved products and Marketing Authorisation Applications for new MAs are required to list certain excipients in the labelling information, as outlined in Directive 2001/83/EC, as amended. These include all excipients for parenteral, ocular and topical products, and specific excipients in other products. These specific excipients are listed in the Annex for ease of access.

What’s new?

The newly added or updated specific excipients listed in the Annex include:

Aspartame (E 951)
Benzalkonium chloride
Benzoic acid (E 210) and benzoates
Benzyl alcohol
Boric acid (and borates)
Cyclodextrins
Fragrances containing allergens
Fructose
Phenylalanine
Phosphate buffers
Propylene glycol (E 1520) and esters of propylene glycol
Sodium
Sodium laurilsulfate (E 487)
Sorbitol (E 420)
Wheat starch (containing gluten)

What do you need to do?

For any of your currently approved products, you should use the first regulatory opportunity to revise any wording in line with the annex. This could be any when you are submitting any variation that involves changing the product information, for instance.

We can help…

Ivowen can advise you on the requirements and assist you with any of the updates and variations that you might have.
Please contact us for further information at any time.

eCTD is coming…

All good (and bad) things, must come to an end.  The NeeS (Non-eCTD electronic submissions) submission format, will no longer be accepted for any Marketing Authorisation applications (MAAs) or submissions in MRP or DCP from 1st January 2018. Centralised Procedure (CP) submissions have been mandatory in eCTD since 2010.  All new MAAs submitted using either the Decentralised Procedure (DCP) or the Mutual Recognition Procedure (MRP), have had to be in eCTD format since the middle of 2015.  As of 1st January 2018, all MRP submissions must be submitted in eCTD.  Therefore, if your application/product is not in eCTD format and you need to submit an MRP variation, you have to transition to eCTD for the next submission.

What is the timetable?

Starting from 1st January 2018 it is mandatory for all CP, DCP and MRP submissions to be in eCTD format.  For national procedures (NP) the deadline is currently set at 1st July 2018 for new MAAs.

Following quickly behind these requirements, all submissions in CP, DCP, MRP and NP will have to be in eCTD from January 2019.  At this stage, the exact date is not confirmed, but you need to be ready.

We can help…

Ivowen can create a baseline dossier for any submission based on currently approved information. Currently, baselines are not mandatory but some Member States are requesting them.  In addition, it is best practise to get your dossier into a baseline for all future submissions.

Ivowen can transition your application to eCTD at the next regulatory activity (variation, renewal, Article 61.3, etc.).

Ivowen can manage the eCTD lifecycle for you in-house and provide you with fully valid, submission-ready sequences.

Contact us for more information or for help with building your eCTD now.

Referrals to the EMA and CHMP? Keep calm and carry on.

What is a Referral all about?

A Referral to the EMA and CHMP is a procedure used to resolve issues such as concerns over the safety or the benefit-risk balance of a medicine or a class of medicines. The matter is ‘referred’ to the European Medicines Agency, so that its expert committees can make a recommendation for a harmonised position across the European Union.
There are a number of reasons why a Referral may be started, ranging from concerns over the safety of a class of medicine to disagreements among Member States on the use of the medicine.
Whatever the reason, your product going to a Referral is a challenging and most probably an unknown (and unwanted) procedure and unfortunately it would seem in recent years Referral procedures have increased, especially Article 29 and Article 30 Referrals.

Recent success with a complicated fixed combination referral

Ivowen recently guided a company through a successful Article 29(4) Referral. This type of Referral is triggered when there is a disagreement between Member States regarding a medicine being evaluated during a mutual-recognition or decentralised procedure, on the grounds of a potential serious risk to public health.
With all the “big players” involved in the concerned decentralised procedure; United Kingdom, Germany, France, Spain, Portugal, Austria, Belgium, Croatia, Ireland, Luxembourg, the Netherlands, this Referral was challenging in more ways than one.

However, on 18 May 2017, the EMA completed the arbitration procedure. The Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of the product outweigh its risks, and the marketing authorisation can be granted. Information regarding this Referral procedure can be found on the EMA website.

Need help with a Referral?

If your products are heading into any Referral, be it an Article 29, 30, 31, 35 or 36, and you need support; from talking you through the complicated timetable, supplying quality and clinical support to the provision of translations why not contact Ivowen to help you through this daunting task?